Our studies comparing and contrasting the pathophysiology of the depression and hypercortisolism in melancholia and Cushing's disease show that hypercortisolism in the former is associated with CRH hypersecretion, while hypercortisolism in the latter is associated with suppression of the PVN CRH neuron as a consequence of long-standing pituitary-mediated hyperadrenalism. While clinical data show that melancholic depression reflects an organized state of hyperarousal and anxiety, our clinical data show that the depressive syndrome associated with Cushing's disease is almost universally an atypical depressive syndrome, associated with lethargy, fatigue, hypersomnia, and hyperphagia. Moreover, follow-up studies of post-operative Cushing's disease patients whose PVN CRH neurons can remain suppressed for several months following surgically-induced remission of hypercortisolism show that as CRH neuron function returns, patients begin manifesting evidence of severe melancholic depression. Studies of other medical syndromes associated with atypical depression also suggest a subtle central pituitary-adrenal insufficiency as a consequence of a PVN CRH deficiency. These include the chronic fatigue syndrome, seasonal affective disorder, and hypothyroidism. To further refine our capacity to detect a subtle central adrenal insufficiency, we have designed and validated a number of new stimuli for the CRH neuron, including the infusion of arginine vasopressin, methoxamine, ipsapirone, procaine, and the application of graded levels of treadmill exercise based on VO2 max. We have tested a number of pharmacologic agents in experimental animals for their capacity to activate the hypothalamic CRH neuron on a chronic basis without tolerance development, and have identified type 1 glucocorticoid receptor antagonists as the most potent. In this regard, we have obtained the genomic clone of the human mineralocorticoid receptor and have sequenced large portions of its 5' regulatory region premonitory to studies exploring more direct ways to manipulate the expression and functional activity of this important regulatory component for the PVN CRH neuron.